2-Cyano-4-fluoropyrrolidine derivative or its salt

ABSTRACT

Provided is a compound having excellent dipeptidyl peptidase IV-inhibiting activity, and a remedy based on the activity for insulin-dependent diabetes (type 1 diabetes), especially for non insulin-dependent diabetes (type 2 diabetes), insulin-resistant disorders, and obesity.

TECHNICAL FIELD

The present invention relates to a novel 2-cyano-4-fluoropyrrolidinederivative or a salt thereof useful as a drug, especially for dipeptidylpeptidase IV (hereinafter referred to as “DPP-IV”) inhibitor and to apharmaceutical composition comprising the compound as an activeingredient.

BACKGROUND ART

Dipetidyl peptidase-IV (DPP-IV) is a serine protease that recognizes andcuts a sequence with proline, hydroxyproline or alanine at the 2ndposition from the N-terminal thereof (H-Xaa-Pro, H-Xaa-Hyp or H-Xaa-Ala,in which Xaa indicates an amino acid). It is known that DPP-IV isbroadly distributed in humans, not only in tissues of the kidneys,liver, and salivary glands, but also in body fluids such as serum,urine, and saliva. Though its physiological role has not been completelyclarified as yet, DPP-IV may participate in regulating biologicalfunctions as it cuts various physiologically-active peptides(non-patentreference 1). In particular, it is now specifically noticed that DPP-IVmay control the activity of a hormone, incretin that participates ininhibiting blood glucose increase.

Incretin is a hormone that is secreted from the intestines afternutrient ingestion in humans, and it acts on pancreatic β-cells toenhance insulin secretion, thereby regulating the blood glucose level.It is known that the incretin activity is attenuated in type 2 diabetics(non-patent reference 2), and it is considered that the activityattenuation will be one reason for the expression of diabetes.Accordingly, it is expected that the postprandial hyperglycemia ofdiabetics could be ameliorated.

At present, glucagon-like peptide (hereinafter referred to as “GLP-1”)is known as a compound that exhibits a most effective incretin activityin humans. GLP-1 is, after secreted in blood, immediately inactivated,and it is known that the inactivation is essentially owing to the actionof DPP-IV that cleaves it (non-patent reference 3). Further, theinactive GLP-1 cleaved by DPP-IV binds to a GLP-1 receptor and preventsactive GLP-1 from binding to the receptor. Accordingly, it is believedthat the incretin action of GLP-1 is thereby attenuated (non-patentreference 4).

For these reasons, it is believed that a DPP-IV inhibitor may preventthe inactivation of GLP-1, therefore enhancing the incretin action ofactive GLP-1, and, as a result, it may prevent the postprandialhyperglycemia of diabetics. In addition, since incretin enhances theglucose-dependent insulin secretion in humans, it is expected that theDPP-IV inhibitor may be a safe remedy without side effect such ashypoglycemia which is often seen in use of existing insulin-secretionremedies.

On the other hand, some 2-cyanopyrrolidine derivatives are known, havinga DPP-IV inhibiting activity (patent references 1 to 7).

Of those, International Publication WO02/30890 pamphlet (patentreference 5) specifically discloses compounds of a general formula (A),saying that the compounds will be effective for prevention and remedy ofdiabetes and for prevention and remedy of other diseases that areinduced or exacerbated by impaired glucose tolerance, hyperinsulinemiaand diabetic complications.

(In the formula, the symbols are as defined in the patent document.)

On the other hand, International Publication WO02/38541 pamphlet (patentreference 6) discloses compounds of a general formula (B), saying thatthe compounds significantly inhibit the blood glucose level increase inan oral glucose tolerance test with Zucker Fatty rats.

(In the formula, the symbols are as defined in the patent document.)

International Publication WO03/002553 pamphlet (patent reference 7)discloses compounds of general formulae (C), (D), (E), (F), (G) and (H),saying that the compounds are useful for treating disorders such asdiabetes, obesity.

(In the formula, the symbols are as defined in the patent document.)

Given that situation, it is greatly desired to develop drugs that havemore excellent DPP-IV inhibiting activity.

Non-patent reference 1: Mentlein R., Regulatory Peptide, 1999, Vol. 85,pp. 9-24.

Non-patent reference 2; Nauck M. A., Diabetologia, 1986, Vol. 29, pp.46-52.

Non-patent reference 3; Drucker D. J., Diabetes, 1998, Vol. 47, pp.159-169

Non-patent reference 4: Knudsen L. B., European Journal of Pharmacology,1996, Vol. 318, pp. 429-435.

Patent reference 1: International Publication WO98/19998 pamphlet.

Patent reference 2: International Publication WO01/96295 pamphlet.

Patent reference 3: International Publication WO00/34241 pamphlet.

Patent reference 4: International Publication WO01/55105 pamphlet.

Patent reference 5: International Publication WO02/30890 pamphlet.

Patent reference 6: International Publication WO02/38541 pamphlet.

Patent reference 7: International Publication WO03/002553 pamphlet.

DISCLOSURE OF THE INVENTION

The present inventors made extensive and intensive investigations withrespect to compounds having a DPP-IV inhibiting activity, which areexpected to be effective for insulin-dependent diabetes (type 1diabetes), non insulin-dependent diabetes (type 2 diabetes),insulin-resistant disorders and obesity. As a result, it has been foundthat a novel 2-cyano-4-fluoropyrrolidine derivative or a salt thereof ofthe invention has an excellent DPP-IV inhibiting activity, leading toaccomplishment of the invention.

Accordingly, the invention provides a 2-cyano-4-fluoropyrrolidinederivative of the following general formula (I) or a pharmaceuticallyacceptable salt thereof that is useful as a DPP-IV inhibitor.

wherein A represents piperidin-4-yl, oxetan-3-yl, pyrrolidin-3-yl,tetrahydro-2H-pyran-4-yl, pyrazolidin-4-yl, 1,3-dioxan-5-yl,8-azabicyclo[3.2.1]oct-3-yl or tetrahydro-2H-thiopyran-4-yl, each ofwhich may be substituted, but excluding piperidin-4-yl which issubstituted with a group selected from the group consisting ofpropane-2-sulfonyl, 2,4,6-trimethylbenzenesulfonyl,phenylmethanesulfonyl, 2-naphthalen-1-ylethanesulfonyl,7,7-dimethyl-6-oxonorbornan-1-ylmethanesulfonyl, 4-fluorophenyl,3,5-difluorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl,4-cyanophenyl, 4-cyano-3-fluorophenyl, 4-cyano-3,5-difluorophenyl,3-cyano-5-fluorophenyl, benzoxazol-2-yl and benzyl; pyrrolidin-3-ylwhich is substituted with a group selected from the group consisting ofpropane-2-sulfonyl, 3-cyanopyridin-6-yl, 4-trifluoromethylphenyl,4-fluorophenyl and 4-fluorobenzyl; and 8-azabicyclo[3.2.1]oct-3-yl whichis substituted with ethoxycarbonyl.

In the formula (I), A is preferably piperidin-4-yl or8-azabicyclo[3.2.1]oct-3-yl, each of which may be substituted, morepreferably a group of a general formula (II):

wherein B represents carbonyl, sulfonyl or single bond;

R¹ represents lower alkyl, aryl or aromatic hetero ring, each of whichmay be substituted;

R² represents lower alkyl which is optionally substituted with a groupselected from the group consisting of —OH and —O-lower alkyl, orrepresents —H.

In formula (II), B is preferably carbonyl or sulfonyl.

In formula (II), R¹ is preferably lower alkyl which is optionallysubstituted, more preferably lower alkyl which is optionally substitutedwith a group selected from the group consisting of —OH and fluoro, evenmore preferably methyl or ethyl, each of which is optionally substitutedwith a group selected from the group consisting of —OH and fluoro, mostpreferably methyl or ethyl, each of which is optionally substituted with—OH.

In formula (II), R² is preferably lower alkyl which is optionallysubstituted with —OH, more preferably methyl or ethyl, each of which isoptionally substituted with —OH, even more preferably methyl, ethyl orhydroxymethyl, most preferably methyl.

The chemical structure of the 2-cyano-4-fluoropyrrolidine derivatives ofthe invention is characterized in that an optionally substitutednon-aromatic hetero ring bonds to the 1-position of a2-cyano-4-fluoropyrrolidine skeleton via aminomethylenecarbonyl, and thepharmaceutical characteristic thereof is that the derivatives have aDPP-IV inhibiting activity.

Of the compounds of formula (I), preferred are those where A ispiperidin-4-yl or 8-azabicyclo[3.2.1]oct-3-yl, each of which isoptionally substituted; more preferred are those where A is a group offormula (II); even more preferred are those where A is a group offormula (II), B is carbonyl or sulfonyl, R¹ is optionally substitutedlower alkyl, R² is methyl, ethyl or hydroxymethyl; and most preferredare those where A is a group of formula (II), B is carbonyl or sulfonyl,R¹ is methyl or ethyl, each of which is optionally substituted with agroup selected from the group consisting of —OH and fluoro, R² ismethyl.

Of those compounds, especially preferred are the following:

4-fluoro-1-({[1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,

4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,

4-fluoro-1-{[(1-glycoloylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,

4-fluoro-1-{[(1-glycoloyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,

4-fluoro-1-{[(1-fluoroacetyl-4-methylpiperidin-4-yl)]amino]acetyl}pyrrolidine-2-carbonitrile,

4-fluoro-1-{[(1-formylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,

4-fluoro-1-{[(1-formyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,or

4-fluoro-1-({[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,or a pharmaceutically acceptable salt thereof;

more preferred are the following:

4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,or

4-fluoro-1-{[(1-glycoloyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment of the compounds of formula (I), A is agroup of formula (II) and B is carbonyl.

The invention further provides a pharmaceutical composition comprising,as an active ingredient, the compound mentioned above, especially apharmaceutical composition comprising, as an active ingredient, thecompound mentioned above for remedies and/or preventives forinsulin-dependent diabetes (type 1 diabetes), non insulin-dependentdiabetes (type 2 diabetes), insulin-resistant disorders or obesity; anda pharmaceutical composition comprising, as an active ingredient, thecompound mentioned above for dipeptidyl peptidase IV inhibitor.

The compounds of the invention will be further described hereinunder.

In this description, “lower alkyl” means a C₁₋₆ linear or branchedalkyl, for example, concretely including methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, neopentyl and hexyl, etc.Preferably, it is methyl, ethyl, propyl or isopropyl, more preferablymethyl or ethyl.

“Aryl” means a C₆₋₁₄ monocyclic to tricyclic, aromatic monovalent groupconsisting of carbon atoms, for example, concretely including phenyl andnaphthyl, etc. Preferably, it is phenyl.

“Aromatic hetero ring” means a monocyclic to tricyclic aromaticmonovalent group having at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulfur atoms, for example, concretelyincluding furanyl, thienyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, isoxazolyl, triazolyl, benzofuranyl,benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl,benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, quinazolyl,quinolyl, isoquinolyl, quinoxayl, imidazopyridinyl andimidazopyrimidinyl, etc. Preferably, it is pyridyl.

The acceptable substituent for the optionally-substituted“piperidin-4-yl, oxetan-3-yl, pyrrolidin-3-yl, tetrahydro-2H-pyran-4-yl,pyrazolidin-4-yl, 1,3-dioxan-5-yl, 8-azabicyclo[3.2.1]oct-3-yl ortetrahydro-2H-thiopyran-4-yl” for A may be any and every one generallyusable for these groups, and the group A may have one or more,preferably from 1 to 4 substituents. Including the carbon atom of A thatdirectly bonds to the group NH in formula (I), the carbon atom or thenitrogen atom of the ring may be substituted. In addition, the sulfuratom of the ring may be oxidized.

The substituent to bond to the carbon atom includes a substituent groupX, —OH, —O—X, halogen, —CO—X, —COO—X, —SO₂—X and —CONRR′. Preferably, itis lower alkyl or aryl, each of which is optionally substituted with oneor more group selected from the group consisting of —OH, —O-lower alkyl,—O-aryl, halogen, cyano and nitro, more preferably lower alkyloptionally substituted with a substituent selected from —OH andfluorine.

R and R′ may be the same or different, representing lower alkyloptionally substituted with —OH, or —H (the same shall applyhereinunder). “Substituent group X” is meant to include lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl,non-aromatic hetero ring and aromatic hetero ring, each of which isoptionally substituted with one or more group selected from the groupconsisting of —OH, —O-lower alkyl, —O-aryl, halogen, cyano and nitro(the same shall apply hereinunder).

On the other hand, the substituent to bond to the nitrogen atom includesa substituent group X, —CO—X, —COO—X, —SO₂—X, and —CONRR′. Preferably,it is lower alkyl, cycloalkyl, aryl or aromatic hetero ring, each ofwhich is optionally substituted with one or more substituent selectedfrom the group consisting of —OH, —O-lower alkyl, —O-aryl, halogen,cyano and nitro; or —SO₂-lower alkyl (optionally substituted with one ormore substituent selected from the group consisting of —OH, —O-loweralkyl, —O-aryl, halogen, cyano and nitro); or —SO₂-aryl (optionallysubstituted with one or more substituent selected from the groupconsisting of —OH, —O-lower alkyl, —O-aryl, halogen, cyano and nitro).

“Lower alkenyl” means a C₂₋₆ alkenyl, for example, concretely includingvinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

“Lower alkynyl” means a C₂₋₆ alkynyl, for example, concretely includingethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

“Cycloalkyl” means a C₃₋₁₄ monovalent residue of a carbon ring, and thismay be bridged fused. Concretely, for example, it includes cyclopropyl,cyclopentyl, cyclohexyl, cyclooctyl, adamantyl, bornyl, norbornyl,bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and bicyclo[3.3.1]nonyl.

“Cycloalkenyl” means a C₃₋₁₄ carbon ring residue that corresponds to the“cycloalkyl” but is partially unsaturated, for example, concretelyincluding cyclopentenyl, cyclohexenyl and norbornenyl.

“Halogen” includes fluoro, chloro, bromo and iodo. Preferably, it isfluoro, chloro or bromo, more preferably fluoro.

The compounds of the invention include mixtures of various stereoisomerssuch as tautomeric isomers and optical isomers, and those isolated fromthem.

The compounds of the invention may form acid-addition salts. Dependingon the type of the substituent therein, they may form salts with bases.Concretely, the salts include acid-addition salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, nitric acid, phosphoric acid, or with organic acids such as formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid; salts with acidic amino acids such as asparticacid, glutamic acid, or with inorganic bases such as sodium, potassium,magnesium, calcium, aluminium, or with organic bases such asmethylamine, ethylamine, ethanolamine; or with basic amino acids such aslysine, ornithine; and ammonium salts.

The compounds of the invention further include hydrates, variouspharmaceutically acceptable solvates, and polymorphic crystals.Naturally, the invention should not be limited to the compoundsdescribed in Examples given hereinunder, and include all derivatives offormula (I) and their pharmaceutically acceptable salts.

Incidentally, the compound of the invention includes all of so-calledprodrugs, i.e., compounds that will be metabolized and converted intothe compound of the foregoing general formula (I) or its salt withinhumans. As the group to form the prodrug are enumerated those groupsdescribed in Prog. Med., 5, 2157-2161 (1985) and Iyakuhin No Kaihatsu(Development of Drugs), Vol. 7, “Molecular Design”, 163-198 (1990), byHirokawa Publishing Co.

(Production Method)

The compound of the invention and its pharmaceutically acceptable saltcan be produced through application of various known synthesis processesby utilizing the characteristic based on the basic skeleton thereof orkinds of the substituents. Incidentally, in some case, it is effectiveon the production technology that depending on the kind of a functionalgroup, the functional group is replaced by a protective group, i.e., agroup that can be readily converted into the functional group in a stateof the starting material or intermediates. Thereafter, if desired, theprotective group is removed, thereby enabling to obtain the desiredcompound. Examples of such a functional group include a hydroxyl group,a carboxyl group and an amino group. Examples of the protective groupthereof include the protective groups as described in Greene and Wuts,Protective Groups in Organic Synthesis (third edition), and these may beproperly used depending on the reaction conditions.

One typical production method is described below.

wherein A has the same meaning as above; and X represents a leavinggroup such as halogen or sulfonyloxy group.

The method comprises alkylation of a compound (II) with an amine (III)of a general formula, A—NH₂ to give the compound (I) of the invention.The reaction may be effected in the absence or presence of a solvent.The solvent may be any of aromatic hydrocarbons such as toluene, xylene;ketones such as methyl ethyl ketone, acetone; ethers such as dioxane,tetrahydrofuran, diglyme; alcohols such as methanol, ethanol,isopropanol; chloroform, methylene chloride, acetonitrile,dimethylformamide, dimethylsulfoxide, water; and their mixed solvents.Depending on the type of the reaction substrate and the reactionconditions, a suitable solvent may be selected for the reaction.

Adding a base to the reaction is preferred for smoothly effecting thereaction. Specific examples of the base are alkali carbonates such assodium carbonate, potassium carbonate; alkali hydrogencarbonates such assodium hydrogencarbonate, potassium hydrogencarbonate; and organicamines such as triethylamine, diisopropylethylamine, pyridine.

Some of the compounds of the invention may be produced from thecompounds (I) obtained in the manner as above, by combining, in anydesired manner, some known steps that may be generally employed by thoseskilled in the art, such as alkylation, acylation, oxidation, reduction,hydrolysis, etc.

Thus produced, the compounds of the invention may be isolated andpurified as they are in the form of free compounds, or after salted intotheir salts in an ordinary manner. The isolation and purification may beeffected in any ordinary chemical operation such as extraction,concentration, distillation, crystallization, filtration,recrystallization, various modes of chromatography, etc.

In case where the compounds of the invention have an asymmetric carbon,they include optical isomers. The optical isomers may be resolved in anordinary manner, for example, through fractionating crystallization withrecrystallization with a suitable salt or through column chromatography.The optical active compounds may be produced, starting from a suitableoptical active compound.

INDUSTRIAL APPLICABILITY

The compounds of the invention have a DPP-IV inhibiting activity.Especially, they have an activity to inhibit the degradation of GLP-1, ahormone that acts on pancreatic β-cells to enhance insulin secretion tothereby regulate blood glucose.

Based on their effect, therefore, the compounds of the invention areuseful for remedy and/or prevention of insulin-dependent diabetes (type1 diabetes), especially non insulin-dependent diabetes (type 2diabetes), insulin-resistant disorders, and obesity.

The excellent DPP-IV inhibiting activity of the compounds of theinvention has been confirmed by the test methods mentioned below.

(1) Test for Determination of DPP-IV Inhibiting Activity:

The reaction was performed in a 96-well flat-bottom microtiter plate. Avarying concentration of the test compound was added to an aqueoussolution comprised of 25 mM Tris-HCl, 140 mM sodium chloride, 10 mMpotassium chloride, 1% RIA-grade bovine serum albumin, and 0.01 mMGly-Pro-AMC (Bachem). To this reaction solution (95 μL/well), added was5 μL of plasma collected from healthy adult volunteers, and incubated atroom temperature for 20 minutes. After the reaction, the fluorescenceintensity (excitation 355 nm/emission 460 nm) of each well was measured(ARVO, Perkin Elmer). The data of 3 wells under the same conditions wereaveraged.

The inhibition in the test group, relative to the solvent-added groupwas calculated, and the IC₅₀ value thereof was obtained through logisticanalysis. The result is given in Table 1. TABLE 1 test compound IC₅₀/nMExample 1 4.2 Example 14 7.2 Example 19 4.2 Example 21 6.0 Example 285.1 Example 34 8.2 Example 36 7.5 Example 41 5.9

The above confirms the DPP-IV inhibiting activity of the compounds ofthe invention.

(2) Test for DPP-IV Inhibiting Activity Duration in Mice:

Male ICR mice (Nippon SLC) were grouped into a test group and a controlgroup of 5 subjects each. A test compound (10 mg/kg) was dissolved inpurified water, and orally administered. Purified water alone was orallyadministered to the mice of the control group. One half, 6, and 12 hoursafter the administration, the blood was collected from each mousethrough the orbital venous plexus thereof. The collected blood wasimmediately centrifuged to isolate the plasma, and the DPP-IV activityof the plasma was measured.

The process of plasma DPP-IV activity determination was as follows: Thereaction was performed in a 96-well plate. 5 μl of the collected plasmawas added to an aqueous solution (95 μl/well) comprises 25 mM Tris-HCl,140 mM sodium chloride, 10 mM potassium chloride, 1% bovine serumalbumin, and 0.01 mM Gly-Pro-AMC (Bachem), and incubated at roomtemperature for 20 minutes. The fluorescence intensity (excitation 355nm/emission 460 nm) of each well was measured (ARVO, Perkin Elmer).

The fluorescent intensity of the well, to which was added the plasmacollected from the control group, was 100%. Based on it, the DPP-IVactivity of the plasma collected from the test compound-administeredmice was calculated, and the activity difference between the controlgroup and the test group was obtained. This indicated the inhibition inthe test group. The result is given in Table 2.

(3) Test for DPP-IV Inhibiting Activity Duration in Rats:

Male SD rats (Clea Japan) were grouped into a test group and a controlgroup of 5 subjects each. A test compound (10 mg/kg) was dissolved inpurified water, and orally administered. Purified water alone was orallyadministered to the rats of the control group. One half, 6, and 12 hoursafter the administration, the blood was collected from each rat throughthe tail vein thereof. The collected blood was immediately centrifugedto isolate the plasma, and the DPP-IV activity of the plasma wasmeasured according to the same process as in the dipeptidyl peptidase-IV(DPP-IV) inhibiting activity duration test shown in (2).

The fluorescent intensity of the well, to which was added the plasmacollected from the control group, was 100%. Based on it, the DPP-IVactivity of the plasma collected from the test compound-administeredrats was calculated, and the activity difference between the controlgroup and the test group was obtained. This indicated the inhibition inthe test group. The result is given in Table 3. TABLE 2 Test for DPP-IVinhibiting activity duration in mice inhibition of plasma inhibition ofplasma DPP-IV activity DPP-IV activity test compound after 6 h/% after12 h/% Example 1 74 59 Example 14 66 65 Example 19 72 61 Example 21 7871 Example 34 85 79 Example 36 81 78 Example 41 83 78

TABLE 3 Test for DPP-IV inhibiting activity duration in rats inhibitionof plasma inhibition of plasma DPP-IV activity DPP-IV activity testcompound after 6 h/% after 12 h/% Example 14 92 87 Example 34 96 94Example 36 92 86 Example 41 93 89 Comparative 65 38 Compound 1Comparative 77 55 Compound 2 Comparative 80 45 Compound 3

In the Table 3, comparative compound 1 represents Example 4-9 describedin patent reference 5, comparative compound 2 represents Example 4-17described in patent reference 5, comparative compound 3 representsExample 33 described in patent reference 7; each patent reference ismentioned above. The structure of comparative compounds 1-3 will beshown below.

Table 2 and Table 3 above show that the compounds of the presentinvention have good oral activities and their activities last even after6 hours and 12 hours from their administration. These results confirmthat the compounds of the present invention have better oral activitiesand duration in vivo in comparison with comparative compounds 1-3.

The pharmaceutical composition that contains, as an active ingredient,one or more of the compounds and their pharmaceutically acceptable saltsof the invention may be prepared by the use of a carrier, a vehicle andother additives generally used in formulating pharmaceuticalcompositions. It may be orally or parenterally administered in any formof tablets, powders, fine granules, granules, capsules, pills, liquids,injections, suppositories, ointments or poultices.

The clinical dose of the compound of the invention may be suitablydetermined, depending on the condition, the body weight, the age and thesex of the patients to which it is administered, but is favorable, ingeneral, from 0.1 to 500 mg/adult/day for oral administration, and from0.01 to 100 mg/adult/day for parenteral administration. This may beadministered to the patients all at a time, or may be divided into a fewportions for administration in a few times. Since the dose variesdepending on various conditions, it may be smaller than the rangementioned above.

As a solid composition for oral administration of the compounds of theinvention, tablets, powders, granules, etc are used. The solidcomposition of those types comprises one or more active substances mixedwith at least one inert diluent, such as lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. In an ordinary manner,the composition may contain any other additives except the inertdiluents noted above, for example, a lubricant such as magnesiumstearate, a disintegrator such as calcium cellulose glycolate, astabilizer such as lactose, and a solubilizer or dissolution promotersuch as glutamic acid or aspartic acid. If desired, the tablets andpills may be coated with a film of sugar or gastric or entericsubstances such as sucrose, gelatin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose phthalate.

A liquid composition for oral administration includes, for example,pharmaceutically-acceptable emulsions, solutions, suspensions, syrups,elixirs and the like, which contain ordinary inactive diluents such aspure water or ethyl alcohol. In addition to the inert diluents, thosecompositions may further contain pharmaceutical aids such assolubilizers, dissolution aids, wetting promoters, suspension promoters,and also sweeteners, flavorings, aromas and preservatives.

Injection for parenteral administration includes, for example,germ-free, aqueous or non-aqueous solutions, suspensions and emulsions.The diluent for the aqueous solutions and suspensions includes, forexample, distilled water and physiological saline for injections. Thediluent for the non-aqueous solutions and suspensions includes, forexample, propylene glycol, polyethylene glycol, vegetable oils such asolive oil, alcohols such as ethyl alcohol, Polysolvate 80 (trade name).

Those compositions may further contain additives such as isotonicityregulators, preservatives, wetting promoters, emulsifiers, dispersants,stabilizers (e.g., lactose), solubilizers, dissolution promoters. Theseare sterilized by filtering them through bacteria-trapping filters, orby adding microbicides thereto, or by exposing them to radiations.Germ-free, solid compositions may be produced previously, and they maybe dissolved in germ-free water or in germ-free solvents for injection,before using them.

BEST MODES OF CARRYING OUT THE INVENTION

The invention is described concretely with reference to the followingExamples, which, however, are not intended to restrict the scope of theinvention. Some starting compounds used in the Examples are novel, andmethods of producing them from known compounds are described asReference Examples.

REFERENCE EXAMPLE 1

A suspension of 1.4 g of (2S,4S)-4-fluoropyrrolidine-2-carboxamidemonohydrochloride prepared according to the similar method as thatdescribed in a patent reference (International Publication WO02/38451pamphlet), and 3.0 ml of N,N-diisopropylethylamine in 10 ml ofchloroform was added dropwise to a solution of 0.73 ml of chloroacetylchloride in 14 ml of chloroform under cooling with an ice-water bath,and the reaction mixture was stirred for 30 minutes under cooling withan ice-water bath. Then, the reaction mixture was concentrated underreduced pressure. To a solution of the resulting residue in 14 ml ofchloroform, 2.4 ml of trifluoroacetic anhydride was added dropwise undercooling with an ice-water bath. Then, the reaction mixture was allowedto room temperature, and stirred for 1 hour. This was concentrated underreduced pressure, and 0.1 M hydrochloric acid was added to the resultingresidue, and this was then extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate. The drying agent wasremoved, and the solvent was removed under reduced pressure. Theresulting residue was purified with silica gel column chromatography(eluent: chloroform to chloroform/methanol=30/1) to obtain 0.84 g of(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile.

NMR: 2.33-2.67 (2H,m), 3.60-4.05 (2H,m), 4.35-4.55 (2H,m), 4.95-5.05,5.30-5.60 (2H,m).

In the same manner as in Reference Example 1, the compounds of ReferenceExamples 2 to 4 shown in Table 4 were prepared from the correspondingstarting compounds.

REFERENCE EXAMPLE 5

To a suspension of 790 mg of tert-butylexo-8-azabicyclo[3.2.1]oct-3-ylcarbamate hydrochloride preparedaccording to the method described in J. Med. Chem. (1991), 34, 656-663or J. Heterocycl. Chem. (1892), 19, 485-488, in 10 ml of methylenechloride and 5 ml of N,N-dimethylformamide, were added 1.3 g oftriethylamine and 1.05 g of methanesulfonyl chloride. The reactionmixture was stirred at room temperature for 1 day and concentrated underreduced pressure. Water was added to the resulting residue, and this wasextracted with ethyl acetate. The organic layer was washed with brine,and then dried over anhydrous magnesium sulfate, and the solvent wasremoved under reduced pressure. The resulting residue was purified withsilica gel column chromatography (eluent: hexane/ethyl acetate=7/3) andcrystallized from diethyl ether-hexane to obtain 600 mg of tert-butylexo-8-(methanesulfonyl)-8-azabicyclo[3.2.1]oct-3-ylcarbamate as acolorless solid.

In the same manner as in Reference Example 5, the compounds of ReferenceExamples 6 to 16 shown in Table 4 were prepared from the correspondingstarting compounds.

REFERENCE EXAMPLE 17

A chloroform solution of 2.0 g of tert-butyl piperidin-4-ylcarbamate wasadded to a mixed solution of 4.7 ml of acetic anhydride and 1.9 ml offormic acid, and the reaction mixture was stirred at room temperaturefor 15 hours. Water was added to the reaction mixture, and this wasextracted with EtOAc. The organic layer was washed with 1 M hydrochloricacid, aqueous saturated sodium hydrogencarbonate and brine. This wasdried with anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The resulting residue was purified with silicagel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 1.7 gof tert-butyl (1-formylpiperidin-4-yl)carbamate.

In the same manner as in Reference Example 17, the compound of ReferenceExample 18 shown in Table 4 was prepared from the corresponding startingcompound.

REFERENCE EXAMPLE 19

To a solution of 3.0 g of tert-butyl piperidin-4-ylcarbamate in 60 ml ofmethylene chloride, were added 2.5 ml of triethylamine, 2.4 g of HOBt,1.3 g of hydroxyacetic acid and 3.5 g of WSCD hydrochloride, and thereaction mixture was stirred at room temperature for 18 hours. 1 Mhydrochloric acid was added to the reaction mixture, and this wasextracted with EtOAc. The organic layer was washed with aqueoussaturated sodium hydrogencarbonate solution, water and brine. This wasdried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The resulting residue was purified with silicagel column chromatography (eluent: chloroform/MeOH=50/1) to obtain 2.8 gof tert-butyl [1-(hydroxyacetyl)piperidin-4-yl]carbamate.

In the same manner as in Reference Example 19, the compounds ofReference Examples 20 to 24 shown in Table 4 were produced from thecorresponding starting compounds.

REFERENCE EXAMPLE 25

A suspension of 1.0 g of tert-butyl piperidin-4-ylcarbamatehydrochloride and 0.6 ml of triethylamine in 15 ml of methylene chloridewas added to a solution of 418 mg of triphosgene in 10 ml of methylenechloride under cooling with ice-water bath. The reaction mixture wasstirred for 2 hours with ice cooling, and then a solution of 358 mg ofpiperidine and 0.6 ml of triethylamine in 5 ml of methylene chloride wasadded thereto and stirred at room temperature for 15 hours. Aqueous 10%citric acid solution was added to the reaction mixture, and this wasextracted with EtOAc. The organic layer was washed with brine, and thendried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The resulting solid was washed with ether toobtain 440 mg of tert-butyl[1-(piperidine-1-carbonyl)piperidin-4-yl]carbamate.

In the same manner as in Reference Example 25, the compounds ofReference Examples 26 and 27 shown in Table 4 were produced from thecorresponding starting compounds.

REFERENCE EXAMPLE 28

2.0 g of m-chloroperbenzoic acid was added to 1.0 g of tert-butyl[1-(thiomorpholine-4-carbonyl)piperidin-4-yl]carbamate in 10 ml ofmethylene chloride under cooling with ice-water bath. The reactionmixture was allowed to room temperature, and stirred for 18 hours.Aqueous saturated sodium thiosulfate solution was added to the reactionmixture, and this was extracted with EtOAc. The organic layer was washedwith aqueous saturated sodium hydrogencarbonate and brine, and driedover anhydrous magnesium sulfate, and the solvent was removed underreduced pressure. The resulting solid was washed with diisopropyl etherto obtain 607 mg of tert-butyl[1-(1,1-dioxothiomorpholine-4-carbonyl)piperidin-4-yl]carbamate.

REFERENCE EXAMPLE 29

A solution of 500 mg of tert-butyl piperidin-4-ylcarbamate and 345 mg ofethyl fluoroacetate in 1 ml of trifluoroethanol was heated under refluxfor 8 hours. The reaction mixture was concentrated under reducedpressure, and 1 M hydrochloric acid was added to the resulting residue.Then, this was extracted with EtOAc, and the organic layer was washedwith aqueous saturated sodium hydrogencarbonate and brine. This was thendried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure. The resulting residue was purified with silicagel column chromatography (eluent: chloroform tochloroform/methanol=30/1) to obtain 345 mg of tert-butyl[1-(fluoroacetyl)piperidin-4-yl]carbamate.

In the same manner as in Reference Example 29, the compound of ReferenceExample 30 shown in Table 4 was produced from the corresponding startingcompound.

REFERENCE EXAMPLE 31

15 ml of 4 M hydrogen chloride in EtOAc was added to a solution of 500mg of the compound of Reference Example 5 in 15 ml of EtOAc, and thereaction mixture was stirred at room temperature for 9 hours. Theresulting solid was collected by filtration to obtain 400 mg of acolorless solid ofexo-8-(methanesulfonyl)-8-azabicyclo[3.2.1]oct-3-ylamine hydrochloride.

In the same manner as in Reference Example 31, the compounds ofReference Examples 32 to 49 shown in Table 4 were produced from thecorresponding starting compounds.

REFERENCE EXAMPLE 50

300 mg of 10% palladium on carbon was added to a solution of 1.4 g ofthe compound of Reference Example 22 in 30 ml of MeOH, and the reactionmixture was stirred overnight under atomospheric hydrogen at roomtemperature. The insoluble matter was removed by filtration, and thefiltrate was concentrated under reduced pressure to obtain 400 mg of acolorless solid of 2-(4-amino-4-methylpiperidin-1-yl)-2-oxoethanol.

In the same manner as in Reference Example 50, the compounds ofReference Examples 51 to 55 shown in Table 4 were produced from thecorresponding starting compounds.

REFERENCE EXAMPLE 56

20 ml of 6 M hydrochloric acid was added to 2.2 g of the compound ofReference Example 42, and the reaction mixture was refluxed for 24hours. The reaction mixture was concentrated, and toluene and MeOH wereadded to the residue, and this was concentrated again. The resultingresidue was crystallized from MeOH-diethyl ether, and collected toobtain 1.22 g of [4-amino-1-(methanesulfonyl)piperidin-4-yl]methanol.

The meanings of the abbreviations in the Table are mentioned below (thesame shall apply hereinunder).

Rf: Number of Reference Example

Salt: salt (HCl: hydrochloride, fum: fumarate, not described: freecompound)

Structure: Structural formula

Data: Physicochemical data (NMR: peak δ [ppm] in ¹H-NMR, in which theinternal standard is (CH₃)₄Si and the solvent for measurement isDMSO-d₆, FAB-MS: FAB mass spectral data, m.p.: melting point)

Me: methyl, Boc: t-butyloxycarbonyl, Ms: methanesulfonyl, Bn: benzylTABLE 4 Rf Structure (Salt) (Data)  1

(FAB-MS:191.)  2

(FAB-MS:191.)  3

(FAB-MS:191.)  4

(FAB-MS:191.)  5

(FAB-MS:305.)  6

(FAB-MS:293.)  7

(FAB-MS:366.)  8

(FAB-MS:293.)  9

(FAB-MS:307.) 10

(FAB-MS:307.) 11

(FAB-MS:265.) 12

(FAB-MS:265.) 13

(FAB-MS:399.) 14

(FAB-MS:355.) 15

(FAB-MS:341.) 16

(FAB-MS:327.) 17

(FAB-MS:229.) 18

(FAB-MS:277.) 19

(FAB-MS:259.) 20

(FAB-MS:287.) 21

(FAB-MS:329.) 22

(FAB-MS:307.) 23

(FAB-MS:329.) 24

(FAB-MS:287.) 25

(FAB-MS:312.) 26

(FAB-MS:328.) 27

(FAB-MS:330.) 28

(FAB-MS:362.) 29

(FAB-MS:261.) 30

(FAB-MS:309.) 31

(HCl) (FAB-MS:205.) 32

(HCl) (FAB-MS:193.) 33

(HCl) (FAB-MS:266.) 34

(HCl) (FAB-MS:193.) 35

(HCl) (FAB-MS:207.) 36

(HCl) (FAB-MS:207.) 37

(HCl) (FAB-MS:129.) 38

(HCl) (FAB-MS:159.) 39

(HCl) (FAB-MS:187.) 40

(HCl) (FAB-MS:165.) 41

(HCl) (FAB-MS:165.) 42

(HCl) (FAB-MS:299.) 43

(HCl) (FAB-MS:212.) 44

(HCl) (FAB-MS:228.) 45

(HCl) (FAB-MS:189.) 46

(HCl) (FAB-MS:189.) 47

(HCl) (FAB-MS:262.) 48

(HCl) (FAB-MS:187.) 49

(HCl) (FAB-MS:161.) 50

(FAB-MS:173.) 51

(FAB-MS:193.) 52

(FAB-MS:207.) 53

(FAB-MS:221.) 54

(FAB-MS:143.) 55

(FAB-MS:174.) 56

(HCl) (FAB-MS:209.)

EXAMPLE 1

To a suspension of 451 mg of 1-(methanesulfonyl)piperidine-4-aminemonohydrochloride prepared according to the method described inInternational Publication WO0218380 pamphlet, and 435 mg of potassiumcarbonate in 8 ml of acetonitrile, was added 200 mg of(2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile, and thereaction mixture was stirred at room temperature for 4 days. Theinsoluble material was removed by filtration, and 1.20 g of silica gelwas added to the filtrate, and the reaction mixture was concentratedunder reduced pressure. The resulting residue was purified with silicagel column chromatography (eluent: chloroform/methanol/aqueous 28%ammonia=100/1/0.1 to 20/1/0.1) to obtain 487 mg of a colorlessamorphous. 10 ml of ethanol was added to the resulting colorlessamorphous, and the reaction mixture stirred at room temperature for 30minutes. The insoluble material was collected by filtration, washed withethanol, and dried under reduced pressure. 230 mg of the resultingcolorless solid was dissolved in 2 ml of tetrahydrofuran and 4 ml ofmethanol, to which was added 80 mg of fumaric acid. The resultingsolution was concentrated under reduced pressure until the amount of thesolvent became about 2 ml, and then 5 ml of ethanol was added to it andthe mixture was stirred at room temperature for 30 minutes. Theprecipitation was collected by filtration, washed with ethanol and driedunder reduced pressure to obtain 217 mg of a colorless crystal of(2S,4S)-4-fluoro-1-({[1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrilemonofumarate.

In the same manner as in Example 1, the compounds of Examples 2 to 47Table 5 and Table 6 were prepared from the corresponding startingcompounds.

The meanings of the abbreviations in the Tables are mentioned below (thesame shall apply hereinunder).

Ex: Number of Example

A: Substituent in general formula

tBu: t-butyl, Et: ethyl, n-Pr: n-propyl, i-Pr: isopropyl, Ac: acetylTABLE 5

Ex A Salt (Data)  1

(fum) (FAB-MS:333.)  2

(fum) (FAB-MS:228.)  3

(fum) (FAB-MS:345.)  4

(fum) (FAB-MS:345.)  5

(fum) (FAB-MS:363.)  6

(fum) (FAB-MS:379.)  7

(fum) (FAB-MS:256.)  8

(fum) (FAB-MS:298.)  9

(fum) (FAB-MS:362.) 10

(fum) (FAB-MS:356.) 11

(fum) (FAB-MS:357.) 12

(fum) (FAB-MS:371.) 13

(fum) (FAB-MS:359.) 14

(fum) (FAB-MS:347.) 15

(fum) (FAB-MS:420.) 16

(fum) (FAB-MS:333.) 17

(fum) (FAB-MS:361.) 18

(fum) (FAB-MS:361.) 19

(fum) (FAB-MS:283.) 20

(fum) (FAB-MS:297.) 21

(fum) (FAB-MS:3 13.) 22

(fum) (FAB-MS:341.) 23

(fum) (FAB-MS:326.) 24

(fum) (FAB-MS:3 19.) 25

(fum) (FAB-MS:3 19.) 26

(fum) (FAB-MS:304.) 27

(fum) (FAB-MS:359.) 28

(fum) (FAB-MS:368.) 29

(fum) (FAB-MS:363.) 30

(fum) (FAB-MS:366.) 31

(fum) (FAB-MS:375.) 32

(fum) (FAB-MS:382.) 33

(fum) (FAB-MS:343.) 34

(fum) (FAB-MS:327.) 35

(fum) (FAB-MS:343.) 36

(fum) (FAB-MS:297.) 37

(fum) (FAB-MS:361.) 38

(fum) (FAB-MS:416.) 39

(fum) (FAB-MS:341.) 40

(fum) (FAB-MS:315.) 41

(fum) (FAB-MS:329.)

TABLE 6 Ex Structure Salt (Data) 42

(fum) (FAB-MS:347.) 43

(fum) (FAB-MS:347.) 44

fum) (FAB-MS:347.) 45

(fum) (FAB-MS:327.) 46

(fum) (FAB-MS:327.) 47

(fum) (FAB-MS:327.)

Hereinafter, the NMR data of some example compounds are shown in Table7. TABLE 7 Ex (Salt) Data  1 NMR: 1.30-1.50(2H, m), 1.65-2.05(2H, m),2.20-2.60(2H, m), 2.60-3.00(6H, m), 3.40-3.85(5H, (fum) m),3.85-4.02(1H, m), 4.90-5.04, 5.30-5.60(2H, m), 6.57(2H, s).  2 NMR:1.95-2.40(2H, m), 3.30-4.30(9H, m), 4.40-4.75, 5.20-5.60(2H, m),6.55(2H, s). (fum)  3 NMR: 1.30-1.50(2H, m), 1.75-1.90(2H, m),1.95-2.15(2H, m), 2.25-2.70(3H, m), 2.75-2.95(2H, (fum) m),3.45-3.60(3H, m), 3.60-3.85(2H, m), 3.85-4.20(1H, m), 4.80-5.38,5.38-5.60(2H, m), 6.56(2H, s), 7.20-7.37(5H, m).  4 NMR: 1.00-1.15(3H,m), 1.45-1.70(1H, m), 1.90-2.10(1H, m), 2.25-2.75(3H, m), 2.75-2.95(2H,(fum) m), 3.12-3.25(1H, m), 3.25-4.10(6H, m), 4.90-5.38, 5.38-5.60(2H,m), 6.58(2H, s), 7.20-7.40(5H, m).  5 NMR: 1.25-2.05(16H, m),2.20-2.90(5H, m), 3.00-4.00(7H, m), 4.75-5.38, 5.38-5.60(2H, m), (fum)6.54(2H, s).  6 NMR: 0.75-0.90(9H, m), 0.90-1.10(2H, m), 1.20-1.55(7H,m), 1.55-2.10(4H, m), 2.10-4.05(10H, (fum) m), 4.60-5.38, 5.38-5.60(2H,m), 6.55(4H, s).  7 NMR: 1.20-1.45(2H, m), 1.70-1.90(2H, m),2.30-2.60(2H, m), 2.60-2.90(1H, m), 3.20-3.35(2H, (fum) m),3.35-3.55(1H, m), 3.55-3.70(2H, m), 3.70-4.05(3H, m), 4.90-5.34,5.34-5.60(2H, m), 6.57(2H, s).  8 NMR: 0.98(6H, t), 2.25-2.80(8H, m),3.00-3.20(2H, m), 3.30-3.80(5H, m), 3.80-4.30(1H, m), (fum)4.70-5.38(1H, m), 5.38-5.65(1H, m), 3.70-4.05(3H, m), 4.90-5.34,5.34-5.60(2H, m), 6.60(4H, s).  9 NMR: 1.35-1.55(6H, m), 2.10-2.45(2H,m), 2.60-2.75(1H, m), 2.98-3.65(4H, m), 3.80-3.95(1H, (fum) m),4.00-4.35(1H, m), 4.70-4.95, 5.15-5.40(3H, m), 6.59(2H, s),7.15-7.45(5H, m). 10 NMR: 1.24-1.50(2H, m), 1.70-2.04(2H, m),2.30-3.04(4H, m), 3.40-4.15(7H, m), 4.90-5.05, (fum) 5.30-5.60(2H, m),6.58(2H, s), 7.02(2H, d), 7.55(2H, d). 11 NMR: 1.20-1.40(2H, m),1.70-2.00(2H, m), 2.30-3.20(4H, m), 3.40-4.10(5H, m), 4.20-4.40(2H,(fum) m), 4.90-5.60(2H, m), 6.57(2H, s), 6.95(1H, d), 7.83(1H, m),8.45(1H, d). 13 NMR: 1.35-1.53(2H, m), 1.55-1.75(2H, m), 1.85-2.05(4H,m), 2.30-2.60(2H, m), 2.88-3.04(4H, (fum) m), 3.35-4.00(4H, m),4.05-4.25(2H, m), 4.90-5.04, 5.28-5.60(2H, m). 14 NMR: 1.05-1.20(3H, s),1.45-1.80(4H, m), 2.30-2.65(2H, m), 2.85(3H, s), 3.00-3.30(4H, m), (fum)3.35-3.85(3H, m), 3.92-4.10(1H, m), 4.97-5.02, 5.30-5.62(2H, m),6.58(2H, s). 15 NMR: 1.25-1.60(2H, m), 1.60-2.05(2H, m), 2.20-2.90(5H,m), 3.00-4.25(6H, m), 4.70-5.00, (fum) 5.20-5.60(2H, m), 6.52(1H, s),7.70-8.00(2H, m), 8.05-8.20(2H, m). 19 NMR: 1.04-1.35(2H, m),1.75-1.95(2H, m), 2.30-2.60(2H, m), 2.65-2.90(2H, m), 3.01-3.10(1H,(fum) m), 3.38-4.05(6H, m), 4.96-5.35, 5.36-5.56(2H, m), 6.58(2H, s),7.97(1H, s). 21 NMR: 1.05-1.40(2H, m), 1.86(2H, br), 2.30-2.65(1H, m),2.77-2.81(2H, m), 2.90-3.05(1H, (fum) m), 3.47-4.16(11H, m), 4.98-5.40,5.34-5.57(2H, m), 6.58(2H, s). 28 NMR: 1.20-1.36(2H, m), 1.72-1.90(2H,m), 2.30-2.62(1H, m), 2.70-2.82(3H, m), 3.05-3.15(4H, (fum) m),3.50-4.00(9H, m), 4.95-5.37(1H, m), 5.40-5.60(1H, m), 6.57(2H, s). 34NMR: 1.05-1.20(3H, s), 1.30-1.70(4H, m), 2.30-2.65(2H, m),3.10-4.10(10H, m), 4.92-5.05, (fum) 5.32-5.62(2H, m), 6.58(2H, s). 36NMR: 1.08, 1.11(3H, s), 1.30-1.65(4H, m), 2.30-2.70(2H, m),3.20-4.10(8H, m), 4.90-5.05, 5.33-5.60(2H, (fum) m), 6.59(2H, s),7.96(1H, s). 41 NMR: 1.06, 1.08(3H, s), 1.38-1.56(4H, m), 2.33-2.67(2H,m), 3.17-4.03(8H, m), 4.98-5.57(4 (fum) H, m), 6.60(2H, s).

Structures of other compounds of the invention will be shown in Table 8.These can be readily prepared according to the production methodsmentioned above, according to the methods described in Examples,according to any other methods obvious to those skilled in the art, oraccording to modifications of those methods.

The meaning of the abbreviation in the Table is mentioned below.

No: Number of Compound TABLE 8

No A No A P1

P2

P3

P4

P5

P6

P7

P8

P9

P11

P11

P12

P13

P14

P15

P16

P17

P18

P19

P20

P21

P22

P23

P24

P25

P26

P27

P28

P29

P30

P31

P32

P33

P34

P35

P36

1. A 2-Cyano-4-fluoropyrrolidine derivative represented by the followinggeneral formula (I) or a pharmaceutically acceptable salt thereof:

wherein A represents piperidin-4-yl, oxetan-3-yl, pyrrolidin-3-yl,tetrahydro-2H-pyran-4-yl, pyrazolidin-4-yl, 1,3-dioxan-5-yl,8-azabicyclo[3.2.1]oct-3-yl or tetrahydro-2H-thiopyran-4-yl, each ofwhich may be substituted, but excluding piperidin-4-yl which issubstituted with a group selected from the group consisting ofpropane-2-sulfonyl, 2,4,6-trimethylbenzenesulfonyl,phenylmethanesulfonyl, 2-naphthalen-1-ylethanesulfonyl, 7,7-dimethyl-6-oxonorbornan-1-ylmethanesulfonyl, 4-fluorophenyl,3,5-difluorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl,4-cyanophenyl, 4-cyano-3-fluorophenyl, 4-cyano-3,5-difluorophenyl,3-cyano-5-fluorophenyl, benzoxazol-2-yl and benzyl; pyrrolidin-3-ylwhich is substituted with a group selected from the group consisting ofpropane-2-sulfonyl, 3-cyanopyridin-6-yl, 4-trifluoromethylphenyl,4-fluorophenyl and 4-fluorobenzyl; and 8-azabicyclo[3.2.1]oct-3-yl whichis substituted with ethoxycarbonyl.
 2. The compound according to claim1, wherein A is piperidin-4-yl or 8-azabicyclo[3.2.1]oct-3-yl, each ofwhich may be substituted.
 3. The compound according to claim 2, whereinA is a group of the following general formula (II):

wherein B represents carbonyl, sulfonyl or single bond; R¹ representslower alkyl, aryl or aromatic hetero ring, each of which may besubstituted; R² represents lower alkyl which is optionally substitutedwith a group selected from the group consisting of —OH and —O-loweralkyl, or represents —H.
 4. The compound according to claim 3, wherein Bis carbonyl or sulfonyl, R¹ is lower alkyl which is optionallysubstituted, R² is methyl, ethyl or hydroxymethyl.
 5. The compoundaccording to claim 4, wherein R¹ is methyl or ethyl, each of which isoptionally substituted with a group selected from the group consistingof —OH and fluoro, and R² is methyl.
 6. The compound according to any ofclaims 1 to 5, which is the following:4-fluoro-1-({[1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,4-fluoro-1-({[4-methyl-1-(methanesulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile,4-fluoro-1-{[(1-glycoloylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,4-fluoro-1-{[(1-glycoloyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,4-fluoro-1-{[(1-fluoroacetyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,4-fluoro-1-{[(1-formylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,4-fluoro-1-{[(1-formyl-4-methylpiperidin-4-yl)amino]acetyl}pyrrolidine-2-carbonitrile,or 4-fluoro-1-({[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile, or a pharmaceutically acceptable saltthereof.
 7. The compounds according to claim 3, wherein B is carbonyl.8. A pharmaceutical composition comprising, as the active ingredient,the compound of claim
 1. 9. The pharmaceutical composition according toclaim 8, which is for remedies for insulin-dependent diabetes (type 1diabetes), non insulin-dependent diabetes (type 2 diabetes),insulin-resistant disorders, or obesity.
 10. The pharmaceuticalcomposition according to claim 8, which is a dipeptidyl peptidase IVinhibitor.